1. Field of the Invention
This invention relates generally to medical apparatus and, more specifically but without limitation, to a system for interacting with the brain of a subject.
2. Description of Related Art
Brain electrical activity (BEA) is a readily accessible and reliable index of brain state and function. It allows distinction between both normal states, such as wakefulness or sleep and its different substates (such as NREM and REM), and abnormal states, such as the ictal and inter-ictal substates of an epileptic brain. BEA is also an important tool for localizing an anatomical substrate of a particular physiological function and for understanding how the function correlates with, or is integrated into, behavior. BEA plays a critical role in the evaluation and treatment of pharmaco-resistant, or intractable, epilepsy, movement disorders, and other neurological diseases. Furthermore, BEA is the basis for real-time automated detection and prediction of the clinical onset of seizures as disclosed in U.S. Pat. No. 5,995,868 issued Nov. 30, 1999 to Ivan Osorio et al, which is incorporated herein by reference. Output from such real-time automated detection and prediction of the clinical onset of seizures provides the cue for delivery of suitable therapeutic means for automated blockage of seizures by either contingent or closed-loop therapy. Closed loop therapy would benefit a significant number of persons with pharmaco-resistant epilepsy, thereby improving quality of life and decreasing morbidity, mortality, and cost of care associated with epilepsy. In addition to epilepsy, recordings and analysis of BEA also plays an increasingly important role in the diagnosis and control of a wide variety of other brain disorders.
Electrical stimulation of brain tissue for prevention, control or blockage of seizures holds promise as a new therapeutic modality. However, electrical stimulation is also a widely utilized tool for the induction of seizures; well known examples are electro-convulsive therapy for mood disorders and an experimental process known as “kindling,” in which repeated delivery of very small currents to an animal's brain eventually results in seizures. Seizure induction or blockage using electrical currents, is multi-factorial depending for instance on the state of excitability of the brain and on the various stimulation parameters such as frequency, intensity and duration, among others. One useful strategy for estimating seizure probability is to assess the degree of excitability of brain tissue. The most common tool to assess this is electrical stimulation; however, since electrical currents can increase or decrease the excitability of brain tissue, they must be used judiciously and with great care to decrease the probability that they would significantly alter excitability in transient or permanent ways, rendering the estimation of seizure probability invalid or superfluous.
Generation of afterdischarges (AD's) to gauge brain excitability, as disclosed in U.S. Pat. No. 6,161,045, issued Dec. 12, 2000 to Robert E. Fischell et al, is possibly the clearest example of an invalid and potentially unsafe use of electrical stimulation. It is invalid because it artificially and markedly alters brain excitability, thus introducing a large bias. The methodology disclosed in therein is a clear illustration, at a macroscopic level, of the Uncertainty Principle: an attempt to measure the state of brain excitability causes large changes therein. It is unsafe because AD's may evolve into seizures and because repeated electrical stimulation of AD's, as required in that teaching, may result in “kindling” which would manifest as an increase in seizure frequency or intensity or as new seizure types through induction of new epileptogenic sites. That is, the reliance of the method disclosed in Fischell et al ('045) on artificially induced AD's may sensitize cortical tissue to generate seizures initially in direct temporal relation to stimulations and eventually independently of electrical stimulation, since their therapy provides for repeated trials of electrical stimulation to induce AD's.
The behavior and properties of brain functions such as degree of excitability, are non-stationary, changing as a function of time, circadian rhythms, attention, activity level and other factors. Exogenous factors such electrical stimulation of sufficient intensity and stimulation to cause afterdischarges AD's are particularly well-suited to alter brain tissue excitability. A rational, safe and fruitful approach is to use non-altering, non-biasing quantifiable indices of inherent brain excitability to deliver electrical stimulation or some other form of therapy in close temporal proximity to the onset of seizures or bursts of epileptiform activity, or during epochs of high probability of seizure occurrence, referred to herein as anticipatory or prophylactic stimulation. More importantly, assessment of brain excitability should not alter, either transiently or permanently, its level or state especially in the direction of excitation, as does elicitation of AD's. The inventive methods disclosed herein to validly assess brain excitability, and to use this information to prevent or block seizures, can be described as follows:                a) Passive: With this method, there is no electrical stimulation or other form of testing. The level of cortical excitability is continuously tracked using appropriate tools. The frequency, duration, intensity and temporo-spatial evolution of endogenous or unprovoked epileptiform or seizure activity are the most reliable and valid indices of degree of brain excitability. Real-time accurate quantification or estimation of these activities may be performed using tools including, but not limited to, tools such as the detection algorithm as disclosed in U.S. Pat. No. 5,995,868, issued Nov. 30, 1999 to Ivan Osorio et al, which computes the “seizure content” in the signal as a finction of time and brain site. The output of said tools may be used to quantify or estimate the probability of state change (i.e., seizure occurrence) over a useful and representative time scale as appropriate (such as minutes, days, or months), depending on (i) each subject and prevailing conditions; (ii) brain excitability and probability of state change of the subject; (iii) circadian variations or other rhythms such as menses (i.e. catamenial epilepsy); and (iv) total sleep time. In the case of epilepsy, the distribution of the seizure content of the brain signal as a function of time, brain site/region and other influences, forms a baseline or control phase. The seizure content is then expressed as a seizure index in terms of the amount of time spent in seizure/unit time, or as any other desired index using measures of central tendencies or other statistical standards, such as probability density functions or other appropriate functions. Significant or meaningful deviations from the baseline (as defined for each individual or condition) may then be used to make decisions regarding timing of delivery of therapy, type of therapy and, in the case of electrical stimulation, intensity, frequency and other relevant parameters. Another approach is to measure inter-seizure (or inter-epileptiform discharge) intervals and use these to develop models to estimate the time of arrival and associated probability of the next seizure and accordingly deliver electrical stimulation or some other form of therapy at times when the probability of the occurrence of a seizure exceeds a pre-determined value. Measurements of seizure or epileptiform activity, as immediately hereinbefore described, may be carried out while the subject is receiving therapy and effects are assessed by comparing indices or probabilities to those observed during the baseline. In the case of electrical stimulation, comparisons of parameters such as waveform (i.e, square waves), intensity (in volts or amperes), frequency, pulse width and duration can be performed to determine efficacy using, for example, seizure index or seizure content of the signal as estimated objectively by application of a detection algorithm and, if appropriate, adjust one or more parameters. This approach increases desired beneficial effects of electrical stimulation or some other form of therapy for seizure blockage while decreasing potentially adverse effects thereof, such as an increase in seizure frequency or induction of new seizure types. Those skilled in the art can appreciate that the probability of seizure occurrence may also be estimated by using the “non-seizure content” of the signal as a function of time, global brain state (i,e., sleep) and site when there is more than one independent potentially epileptogenic site (right vs. left mesial temporal regions for example). It also worth mentioning out that the concepts, methods and tools used to estimate probability of seizure occurrence may be applied to biological state changes in general with appropriate modifications.        
Measurement of naturally occurring chemicals or compounds such as calcium ions, calmodulin binding protein, or of neurotransmitters such as GABA or glutamate may be used alone or in conjunction with electrical activity, temperature, etc., to estimate degree of brain excitability and, indirectly, seizure probability. Other factors that may alter brain excitability, such as total sleep time or level of activity for example, may be entered into the analysis to improve estimation of state change (i.e., seizure probability).                b) Active: Ultrasound, Doppler, light pulses (i.e., near infrared) or paired pulse stimulation, which have a negligible probability of inducing AD's, are potentially useful tools to assess degree of brain or cortical excitability. Excitability testing may be performed continuously, periodically, randomly or based on a subject's seizure probability record based on electrical, chemical or other types of signals.        
Stimulation Methodologies.
Electrical stimulation is an emerging therapy for seizures even though the dynamics of seizures and epilepsy are still poorly understood. Brain electrical stimulation at frequencies above 100 Hz has a therapeutic effect on tremor and other manifestations of Parkinson's disease in humans. Additional evidence from human and animal applications indicates that beneficial effects may also be obtained from stimulation at higher frequencies. For example, high frequency electrical stimulation of rat cerebral cortex simultaneously up-regulates the expression of glutamic acid decarboxylase, which is the enzyme involved in the synthesis of GABA, which is the main inhibitory brain neurotransmitter, and down-regulates calciun/calmodulin dependent protein kinase II expression, which enhances neuronal excitability. The net effect of these changes is to decrease cortical excitability and with it the probability of seizure generation. Charged-balanced square-wave pulses above 100 Hz, delivered in response to automated seizure detections using a validated algorithm, see Osorio et al ('868), decrease seizure frequency, intensity or duration in humans without causing adverse effects. Furthermore, unlike stimulation at 50-60 Hz, the higher frequencies elicit after-discharges only very infrequently, which suggests they do not excite brain tissue. However, there is also preliminary evidence that low frequency stimulation (˜1 Hz) reduces the probability of seizure generation.
Frequency (f) of stimulation is only one of several parameters that may shape the direction of a response (excitation vs. inhibition or depression) of nervous tissue. Other parameters are: duration of stimulation (t), intensity (I), pulse width (p), waveform (w), slopes (S) of the rising and descending components of the pulse, polarity (P) of the initial phase of the pulse, and orientation of the electrical field (O) in reference to the epileptogenic site.
U.S. Pat. No. 5,938,689, issued Aug. 17, 1999 to Robert E. Fischell et al, is an example of a prior art implantable electrical stimulation system for the treatment of neurological disorders such as epilepsy or migraine based on the concept of generation of a “current curtain” to contain abnormal brain activity, which has several important limitations:
(a) The degree of spatial and temporal resolution required to generate a “current curtain” to contain seizure spread is unattainable as recording or sensing is done from the cortical surface from where precise localization of seizure onset is not possible. For a further discussion of the limitations of recording BEA only from the cortical surface, see U.S. Pat. No. 7,006,859 entitled “Unitized Electrode with Three-Dimensional Multi-Site, Multi-Modal Capabilities for Detection and Control of Brain State Changes” and filed concurrently herewith.                (ii) Given the limited spatial resolution of the Fischell et al method, the probability that the tissue, which generates spontaneous seizures, overlaps or is fully congruous with the tissue that is excited to generate after-discharges as required for efficacy, is low. The limited spatial resolution is further compounded by the fact that Fischell et al teaches the use of separate detection and stimulation electrodes which, although not taught by that reference, must be perfectly aligned in the radial direction to avoid unnecessary impairment of temporal resolution with resultant undesired delay of detection and intervention. The end result is that electrical stimulation as taught by Fischell et al is unlikely to be delivered to the seizure onset site with the degree of precision required to be efficacious and the built-in delay between detection and stimulation may be such that the proposed “curtain” of electrical current, even if effective which is unlikely, will not be set in a timely manner. Therefore, the validity of the premise upon which the Fischell et al method rests, is questionable; and        (ii) certain histological and electrical properties of brain tissue make the concept of “curtain” for control of epileptic seizures not reducible to practice. For example, brain tissue is neither homogeneous nor isotropic, which is likely to result in unevenness in current density, direction and velocity of formation of the “curtain,” which may allow passage of seizure activity into surrounding tissue. Also, due to the anisotropy of brain tissue, the axis of polarization is unlikely to be uniform or have the same orientation for all stimulated tissue, a factor that decreases efficacy since the orientation of this axis in relation to the anatomical orientation of the neuropil determines the degree or extent of the effect on neuronal activity.        
(b) The teachings of Fischell et al. ('689) are based on the idea of creating a sheet current of enough intensity to depolarize the neurons so that they form a rigid boundary of any epileptic activity. Without the existence of a closed boundary around the estimated location of the focus, this is practically impossible because it needs the presence of unrealistically large implanted electrodes.
(c) The cortex contains both excitatory and inhibitory neurons. The “curtain,” if effective, will not only encompass excitatory but also inhibitory interneurons which, if “blocked,” will facilitate spread of seizures by decreasing “surround inhibition,” a paradox apparently not addressed or recognized in the Fischell et al teachings.
(d) According to Fischell et al. ('689), the electrical field density drops as a function of distance from the “curtain.” As a result, the membrane potential of neurons enveloped by the “curtain” will be depolarized at different levels in reference to their threshold for generating action potentials. One consequence of such electrical inhomogeneity is that neurons at the outer edges may have sub-threshold depolarization, leading to the well-known phenomenon of facilitation which, instead of decreasing, will increase seizure spread. The spread may be directed to other cortical regions or to subcortical structures, such as the thalamus, setting up cortico-thalamo-cortical volleys which may increase cortical excitability and facilitate undesired secondary generalization of focal seizures.
(e) Fischell et al '689 does not teach which electrode is connected positively (+) and which is connected negatively (−), which can be a critical factor in determining direction and extent of current flow and field geometry, which determines efficacy. It is known that depolarization occurs below the cathode first. Thus, making the deeper electrode positive will delay the formation of the “curtain” and may result in seizure spread beyond the “curtain.” Hence details on the polarities are an important part of utilizing such a device.
(f) The current density in brain tissue is not uniform along the path of the current flow and hence the path is not a straight line. For example, the current density is highest near the electrodes in case of bipolar stimulation. Consequently, formation of a “curtain” of depolarization is difficult to attain and impossible to be certain as to its location. While the “shape” of an epileptic “focus” is not known, it is highly unlikely that it can be described by straight lines as suggested by Fischell et al ('689). In addition, that reference does not teach: (i) critically important parameters such as duration of the “curtain” required to block and prevent recurrence; nor (ii) how to depolarize in a “sheet-like” manner, rather than in bulk, the involved tissue. The incomplete understanding exhibited in Fischell et al '689 is underscored by statements therein, such as: “As shown in FIGS. 4A, 4B and 4C each electrode could be within or outside the boundary 14 of an epileptic focus, or the electrode could be placed exactly on the boundary 14” (column 4, lines 33-36). Precise delineation of an “epileptic focus” is not possible using electrodes and methods as described therein. Furthermore, the “boundaries” of an “epileptic focus” are not “fixed” but probably vary as a function of neuronal and network excitability which, in turn, vary across the sleep-wake cycle and as a function of other factors, such as light intensity, level of attention, level of activity, availability of energy substrates, etc. The instability of the “boundaries of the epileptic focus” is further increased by the generation of the after-discharges called for in the teachings of Fischell et al ('045).
(g) The total number of separate electrodes and tracks left by the insertion process in Fischell et al ('689) required for seizure detection and EBS (see column 4, lines 7-11) is more than those required by the teachings herein and those of U.S. pat. Ser. No. 7,006,859 entitled “Unitized Electrode with Three-Dimensional Multi-Site, Multi-Modal Capabilities for Detection and Control of Brain State Changes,” filed concurrently herewith. The Fischell et al teaching of separate sensing and stimulating units adds unnecessary bulk and processing complexity. The therapeutic ratio of such an arrangement, defined as benefits/adverse effects or therapeutic ratio, appears to be unacceptably low, in light of the spatial incongruence and temporal delay that the Fischell et al approach introduces and the bilk/complexity mentioned immediately hereinbefore.
What is needed is a methodology for automatic and quantitative assessment of cortical excitability using means/methods that do not alter that cortical excitability; a methodology for assessment of cortical excitability using multiple indices such as electrical activity, concentration of chemicals, responses to ultrasound or near-infra-red light, changes in temperature, etc.; a methodology having the ability to automatically quantify the effect of individual electrical stimulation parameters or sets of parameters; a methodology having the ability to automatically remove/delete, add and rank individual parameters or set of parameters according to efficacy; and a methodology having the ability to automatically tailor the response to each subject, taking into account circadian or ultradian variations in cortical excitability, exogenous or endogenous factors which may alter it, etc.